Colorectal cancer is the second leading cause of death due to cancer in both men and women in the United States: in 1990, and estimated 60,900 Americans died from cancers of the colon or the rectum, while an additional 155,000 new cases were diagnosed. Clearly the prevention and early detection of colorectal represent high research priorities, both of which have been addressed in the current proposal. In the field of prevention, chemopreventive agents have shown promise in reducing the incidence of cancer. Of the several nutritional variables, dietary fat has received the strongest experimental evidence as a modulator of tumor growths. Not only is total fat intake epidemiologically correlated with several cancers in human, but fatty acid composition also exerts a measurable impact on tumor initiation and growth. Omega-3 fatty acids found in fish oils inhibit the synthesis of prostaglandins and thromboxanes of the 2-series, which are strongly correlated with carcinogenesis. The proposed randomized, double-blind pilot clinical trial will attempt to isolate the ability of fish oil supplementation (10 g/d) as part of a healthy diet and thus to test the hypothesis that fish oil supplementation decreases the proliferation potential of colon crypt cells in individual previously diagnosed with Dukes' A and B1 colon cancer. Blindness will be maintained by use of tasteless, ordorless fish oil and placebo supplements dispensed as a foam that can be consumed directly or spread on foods (1 tsp BID= 10 g). Compliance will be monitored through food records and 24-hour recalls and by gas chromatographic analysis of platelet and red blood cell phospholipid fatty acid profiles, which can indicate within one week of supplementation whether patients are consuming the fish oil. Body weight, total fat intake, fiber intake, and micronutrient levels will be controlled throughout the one-year trial. Tissue from rectal biopsies taken at baseline and at six and twelve months will be analyzed for cellular hyperproliferation. Assessment of colon cell proliferation will include measurement of labeling index and DNA synthesis time of isolated crypt cells by use of bromodeoxyuridine labeling and of bivariate DNA/BrdUrd flow cytometric analysis; identification of the proliferating crypt compartment will be achieved through histological localization of PCNA along the crypt length. The specificity and sensitivity of this method for assessing colon proliferation potential as a marker of increased risk for colon cancer will be analyzed in reference to similar measurements obtained from 15 Seventh-Day Adventists volunteers. Multi-parameter flow cytometry to measure correlated cellular RNA, DNA, and protein in colon cells will also be developed; tissue specimens from patients undergoing surgical treatment of colon cancer will be used in this work during the first six months of the proposed study. Characterization of cytoplasmic changes in proliferating colon cells may further enhance the study of intermediate markers in colon cancer.
| Huang, Y C; Jessup, J M; Forse, R A et al. (1996) n-3 fatty acids decrease colonic epithelial cell proliferation in high-risk bowel mucosa. Lipids 31 Suppl:S313-7 |
| Blackburn, G L; Giardiello, F M (1995) Developing strategies for intervention/prevention trials of individuals at risk of hereditary colon cancer. J Natl Cancer Inst Monogr :107-10 |
